Abstract
Malaria parasite UIS3 (up-regulated in infective sporozoites gene 3) is essential for sporozoite development in infected hepatocytes. UIS3 encodes for a membrane protein that is localized to the parasite parasitophorous vacuolar membrane in infected hepatocytes. We describe here 2.5-Å resolution crystal structure of Plasmodium falciparum UIS3 soluble domain (PfUIS3130-229) in complex with the lipid phosphatidylethanolamine (PE). PfUIS3130-229 is a novel, compact, and all α-helical structure bound to one molecule of PE. The PfUIS3130-229-PE complex structure reveals a novel binding site with specific interactions between PfUIS3130-229 and the PE head group. One acyl chain of PE wraps around part of PfUIS3130-229 and docks onto a hydrophobic channel. We additionally provide new structural and biochemical evidence of PfUIS3130-229 interactions with lipids (phosphatidylethanolamine), with phospholipid liposomes, and with the human liver fatty acid-binding protein. The direct interaction of PfUIS3130-229 with liver fatty acid-binding protein most likely provides the parasite with a conduit for importing essential fatty acids/lipids. Therefore, our analyses have implications for lipid transport into the parasite during the rapid growth phases of sporozoites. Given that PfUIS3 is essential for establishment of liver stage infection by P. falciparum, our data provide a new target for abrogating parasite development within liver cells before typical symptoms of malaria can manifest.
Highlights
Plasmodium parasites are causative agents of malaria, which affects Ͼ500 million people and claims ϳ2 million lives annually [1]
UIS3 gene encodes a malaria parasite specific, unique, membrane-bound protein localized to the sporozoite parasitophorous vacuolar membrane (PVM)4 [4]
Studies using the yeast two-hybrid system and co-immunoprecipitation experiments have recently suggested that Plasmodium yoelii UIS3 protein is capable of binding to the mouse liver fatty acid-binding protein (LFABP) [4]
Summary
Plasmodium parasites are causative agents of malaria, which affects Ͼ500 million people and claims ϳ2 million lives annually [1]. Such of a lipophilic channel very near to PE binding channel (Fig. 7).This channel is lined by residues Leu134, Ile132, Phe188, Leu192, Leu158, and Leu161, which are largely conserved in all liposome decoration with PfUIS3130–229 may mimic the interaction of PfUIS3130–229 with parasite PVM, an event likely to facilitate transfer of fatty acid/lipid cargo directly on to the parthe plasmodial UIS3.
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